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L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling

BACKGROUND: Although codeine has been reported to enhance sexual activity by improving penile reflexes, it has been shown to impair fertility indices. Also, codeine impairs ovarian steroidogenesis and folliculogenesis. Nonetheless, whether or not codeine exerts an epigenetic effect remains unclear....

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Autores principales: Akhigbe, Roland Eghoghosoa, Afolabi, Oladele A., Ajayi, Ayodeji F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469994/
https://www.ncbi.nlm.nih.gov/pubmed/36099318
http://dx.doi.org/10.1371/journal.pone.0274411
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author Akhigbe, Roland Eghoghosoa
Afolabi, Oladele A.
Ajayi, Ayodeji F.
author_facet Akhigbe, Roland Eghoghosoa
Afolabi, Oladele A.
Ajayi, Ayodeji F.
author_sort Akhigbe, Roland Eghoghosoa
collection PubMed
description BACKGROUND: Although codeine has been reported to enhance sexual activity by improving penile reflexes, it has been shown to impair fertility indices. Also, codeine impairs ovarian steroidogenesis and folliculogenesis. Nonetheless, whether or not codeine exerts an epigenetic effect remains unclear. On the other hand, arginine has been speculated to enhance penile reflexes by upregulating NO/cGMP Signaling. AIM: The study evaluated the effect of maternal codeine exposure and prepubertal codeine and arginine treatments on F1 male sexual function and fertility indices, as well as the outcome of F2 progenies. In addition, the epigenetic programming mechanism was also explored. METHODS: Forty three-week-old female rats were randomized into two groups (n = 20 rats/group); the control that received 0.5 ml of distilled water and the codeine-treated that received 5 mg/kg of codeine via gavage for eight weeks. Afterward, the female rats were paired for mating with sexually mature male rats. Rats were maintained on their pre-pregnancy treatments throughout pregnancy and lactation. FI progenies from each cohort (control and codeine-treated cohorts) were weaned at three weeks and randomized into four groups; the control, codeine-treated, L-arginine-treated (300mg/kg), and codeine + L-arginine-treated (n = 10 rats/group). Administration commenced a week post-weaning and lasted for eight weeks via gavage. KEY FINDINGS: Maternal codeine exposure did not alter body weight, but significantly reduced anogenital distance and anogenital index of F1 male offspring. Also, maternal codeine delayed preputial membrane separation, impaired male sexual competence, and penile reflexes of F1 male offsprings. These were associated with reduced dopamine, gonadotropins, and testosterone levels as well as suppressed expression of androgen receptor mRNA. In addition, maternal codeine downregulated NO/cGMP signaling, impaired fertility indices, and reduced the litter size, weight, and survival of F2 progenies. These alterations were observed to be aggravated by prepubertal codeine exposure but improved by prepubertal arginine treatment. SIGNIFICANCE: In conclusion, codeine programmed sexual dysfunction by suppressing the levels of dopamine and testosterone, as well as repressing the expression of androgen receptor mRNA. In addition, codeine-induced epigenetic reprogramming was expressed in the F2 offsprings as reduced litter size and weight, and survival rate. Notably, these observations were worsened by prepubertal codeine exposure, but dampened by prepubertal arginine treatment.
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spelling pubmed-94699942022-09-14 L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling Akhigbe, Roland Eghoghosoa Afolabi, Oladele A. Ajayi, Ayodeji F. PLoS One Research Article BACKGROUND: Although codeine has been reported to enhance sexual activity by improving penile reflexes, it has been shown to impair fertility indices. Also, codeine impairs ovarian steroidogenesis and folliculogenesis. Nonetheless, whether or not codeine exerts an epigenetic effect remains unclear. On the other hand, arginine has been speculated to enhance penile reflexes by upregulating NO/cGMP Signaling. AIM: The study evaluated the effect of maternal codeine exposure and prepubertal codeine and arginine treatments on F1 male sexual function and fertility indices, as well as the outcome of F2 progenies. In addition, the epigenetic programming mechanism was also explored. METHODS: Forty three-week-old female rats were randomized into two groups (n = 20 rats/group); the control that received 0.5 ml of distilled water and the codeine-treated that received 5 mg/kg of codeine via gavage for eight weeks. Afterward, the female rats were paired for mating with sexually mature male rats. Rats were maintained on their pre-pregnancy treatments throughout pregnancy and lactation. FI progenies from each cohort (control and codeine-treated cohorts) were weaned at three weeks and randomized into four groups; the control, codeine-treated, L-arginine-treated (300mg/kg), and codeine + L-arginine-treated (n = 10 rats/group). Administration commenced a week post-weaning and lasted for eight weeks via gavage. KEY FINDINGS: Maternal codeine exposure did not alter body weight, but significantly reduced anogenital distance and anogenital index of F1 male offspring. Also, maternal codeine delayed preputial membrane separation, impaired male sexual competence, and penile reflexes of F1 male offsprings. These were associated with reduced dopamine, gonadotropins, and testosterone levels as well as suppressed expression of androgen receptor mRNA. In addition, maternal codeine downregulated NO/cGMP signaling, impaired fertility indices, and reduced the litter size, weight, and survival of F2 progenies. These alterations were observed to be aggravated by prepubertal codeine exposure but improved by prepubertal arginine treatment. SIGNIFICANCE: In conclusion, codeine programmed sexual dysfunction by suppressing the levels of dopamine and testosterone, as well as repressing the expression of androgen receptor mRNA. In addition, codeine-induced epigenetic reprogramming was expressed in the F2 offsprings as reduced litter size and weight, and survival rate. Notably, these observations were worsened by prepubertal codeine exposure, but dampened by prepubertal arginine treatment. Public Library of Science 2022-09-13 /pmc/articles/PMC9469994/ /pubmed/36099318 http://dx.doi.org/10.1371/journal.pone.0274411 Text en © 2022 Akhigbe et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Akhigbe, Roland Eghoghosoa
Afolabi, Oladele A.
Ajayi, Ayodeji F.
L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling
title L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling
title_full L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling
title_fullStr L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling
title_full_unstemmed L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling
title_short L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling
title_sort l-arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and no/cgmp signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9469994/
https://www.ncbi.nlm.nih.gov/pubmed/36099318
http://dx.doi.org/10.1371/journal.pone.0274411
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